Osteoarthritis: An update with relevance for clinical practice

Abstract

Osteoarthritis is thought to be the most prevalent chronic joint disease. The incidence of osteoarthritis is rising because of the ageing population and the epidemic of obesity. Pain and loss of function are the main clinical features that lead to treatment, including non-pharmacological, pharmacological, and surgical approaches. Clinicians recognise that the diagnosis of osteoarthritis is established late in the disease process, maybe too late to expect much help from disease-modifying drugs. Despite efforts over the past decades to develop markers of disease, still-imaging procedures and biochemical marker analyses need to be improved and possibly extended with more specific and sensitive methods to reliably describe disease processes, to diagnose the disease at an early stage, to classify patients according to their prognosis, and to follow the course of disease and treatment effectiveness. In the coming years, a better definition of osteoarthritis is expected by delineating different phenotypes of the disease. Treatment targeted more specifically at these phenotypes might lead to improved outcomes.

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Lancet 2011; 377: 2115–26
See Comment page 2067
This is the fi rst in a Series of
three papers about arthritis
Department of Rheumatology
and Clinical Immunology,
University Medical Centre
Utrecht, Utrecht, Netherlands
(Prof J W J Bijlsma MD,
F P J G Lafeber PhD); and
Department of Rheumatology,
Pierre and Marie Curie
University, Hospital
Saint-Antoine, Paris, France
(F Berenbaum MD)
Correspondence to:
Prof Johannes W J Bijlsma,
University Medical Centre
Utrecht, Department of
Rheumatology and Clinical
Immunology, PO Box 85.500,
Utrecht, 3508 GA, Netherlands
j.w.j.bijlsma@umcutrecht.nl
Arthritis 1
Osteoarthritis: an update with relevance for clinical practice
Johannes W J Bijlsma, Francis Berenbaum, Floris P J G Lafeber
Osteoarthritis is thought to be the most prevalent chronic joint disease. The incidence of osteoarthritis is rising
because of the ageing population and the epidemic of obesity. Pain and loss of function are the main clinical features
that lead to treatment, including non-pharmacological, pharmacological, and surgical approaches. Clinicians
recognise that the diagnosis of osteoarthritis is established late in the disease process, maybe too late to expect much
help from disease-modifying drugs. Despite eff orts over the past decades to develop markers of disease, still-imaging
procedures and biochemical marker analyses need to be improved and possibly extended with more specifi c and
sensitive methods to reliably describe disease processes, to diagnose the disease at an early stage, to classify patients
according to their prognosis, and to follow the course of disease and treatment eff ectiveness. In the coming years, a
better defi nition of osteoarthritis is expected by delineating diff erent phenotypes of the disease. Treatment targeted
more specifi cally at these phenotypes might lead to improved outcomes.
Introduction
Epidemiology
The prevalence of osteoarthritis is dependent on the
precise defi nition used and on the site of interest. The
knee, hip, and hand are most aff ected by the disease
(fi gure 1). Osteoarthritis becomes more common with
age, and after age 50 years more women than men are
aff ected. For example, the Rotterdam study1 of a
population-based cohort of 3906 people 55 years or older
reported that 67% of women and 55% of men had
radiographic osteoarthritis of the hand. In people older
than 80 years, 53% of women and 33% of men had
radiographic osteoarthritis of the knee. The age-
standardised and sex-standardised incidence of osteo-
arthritis of the hand is 100 per 100 000 person-years, for
the hip is 88 per 100 000 person-years, and for the knee is
240 per 100 000 person-years.2
Osteoarthritis in general develops progressively over
several years, although symptoms might remain stable
for long periods within this period. The diagnosis of the
disease relies on clinical and radiological features
(panel).3 Nearly half of patients with radiological features
of osteoarthritis have no symptoms and vice versa. Risk
factors for occurrence and progression of osteoarthritis
have been identifi ed, and diff er on the basis of the joints
involved (table 1).3
Pathology
In addition to the involvement of several joint tissues,
osteoarthritis has long been mainly characterised by a
failure of the repair process of damaged cartilage due to
biomechanical and biochemical changes in the joint.
Cartilage is non-vascularised, so this restricts the supply
of nutrients and oxygen to the chondrocytes—the cells
that are responsible for the maintenance of a very large
amount of extracellular matrix. At an early stage, in an
attempt to eff ect a repair, clusters of chondrocytes form
in the damaged areas and the concentration of growth
factors in the matrix rises.4,5 This attempt subsequently
fails and leads to an imbalance in favour of degradation.
Increased synthesis of tissue-destructive proteinases
(matrix metalloproteinases and agrecanases),6,7 increased
apoptotic death of chondrocytes, and inadequate
synthesis of components of the extracellular matrix, lead
to the formation of a matrix that is unable to withstand
normal mechanical stresses. Consequently, the tissue
enters a vicious cycle in which breakdown dominates
synthesis of extracellular matrix. Since articular cartilage
is aneural, these changes do not produce clinical signs
unless innervated tissues become involved. This is one
reason for the late diagnosis of osteoarthritis.
Although the pathophysiology of osteoarthritis has
long been thought to be cartilage driven, recent evidence
shows an additional and integrated role of bone and
synovial tissue, and patchy chronic synovitis is evident in
the disease.8 Synovial infl ammation corresponds to
clinical symptoms such as joint swelling and
infl ammatory pain, and it is thought to be secondary to
cartilage debris and catabolic mediators entering the
synovial cavity. Synovial macrophages produce catabolic
and proinfl ammatory mediators and infl ammation starts
negatively aff ecting the balance of cartilage matrix
degradation and repair.9 This process in turn amplifi es
synovial infl ammation, creating a vicious cycle. Synovial
infl ammation happens in early as well as late phases of
osteoarthritis and is seldom as severe as in rheumatoid
Search strategy and selection criteria
The information in our paper is primarily based on PubMed
searches with the terms “osteoarthritis” in combination with
“cartilage”, “bone”, “synovitis”, “imaging”, “biomarker”, and
“treatment”. We mainly included papers from the past
5 years, with the addition of highly regarded older papers. We
also included some review articles and book chapters as
comprehensive overviews, the details of which are beyond
the scope of our report.

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arthritis, but it might add to the vicious cycle of
progressive joint degeneration.
The main characteristics of osteoarthritis are changes
in the subchondral bone. Osteophyte formation, bone
remodelling, subchondral sclerosis, and attrition are
crucial for radiological diagnosis. Several of these bone
changes take place not only during the fi nal stage of the
disease, but also at the onset of the disease—possibly
before cartilage degradation.10,11 This fi nding led to the
suggestion that subchondral bone could initiate
cartilage damage.
Clinical features and diagnosis
Pain is the fi rst and predominant symptom of
osteoarthritis that causes patients to visit their family
doctor. The pain experienced is intermittent, typically
worst during and after weight-bearing activities.
Infl ammatory fl ares can happen during the course of the
disease. Patients with osteoarthritis also experience
stiff ness: in the morning, after a period of inactivity, or
particularly in the evening. This stiff ness generally
resolves in minutes, unlike the prolonged (usually
>30 min) stiff ness caused by rheumatoid arthritis.
Loss of movement and function is another reason
patients visit their family doctor. Patients report
symptoms that limit their day-to-day activities, such as
stair climbing, walking, and doing household chores.
Symptomatic osteoarthritis might be associated with
depression and disturbed sleep, which additionally
contribute to disability. The symptoms of osteoarthritis
diminish the patients’ quality of life.12
Physical examination is needed to confi rm and
characterise joint involvement, and to exclude pain and
functional syndromes with other causes—eg, in-
fl ammatory arthritis.13 Joint enlargement results from
joint eff usion, bony swelling, or both. A synovial eff usion
might not only be identifi ed during osteoarthritis fl ares,
but also during chronic phases as a persistent feature.
Restricted passive movement can be the fi rst and sole
physical sign of symptomatic disease. Bursitis, tendinitis,
muscle spasm, and tissue response to, for instance,
damaged meniscus can cause the same pain syndrome
and must be carefully sought during examination.
Crepitus, a sensation of crunching or crackling, is
commonly felt on passive or active movement of a joint
with osteoarthritis. Joint deformities relate to advanced
disease with joint damage that involves cartilage,
periarticular bone, synovium, articular capsule,
ligaments, and muscles (fi gure 2). A joint can lock if
loose bodies or fragments of cartilage (or meniscus) get
into the joint space. Caution should be exercised to
correctly attribute pain to the correct site—eg, patients
with osteoarthritis of the hip might report knee pain
because of referred pain or anserine bursitis. Additional
neurological and spine examination is often needed.
Imaging investigations are seldom needed to confi rm
the diagnosis; they might be useful to establish the
severity of joint damage and to monitor disease
progression. However, some sites and clinical scenarios
need imaging assessment (including MRI or scintigraphy)
to exclude other diseases, including avascular
osteonecrosis, Paget’s disease, complex regional pain
syndrome, infl ammatory arthropathies, and stress
fractures. Also, blood tests are not routinely needed in
cases of uncomplicated chronic pain arising from clearly
defi ned osteoarthritis. ESR and C-reactive protein are
usually within the normal range. Some laboratory tests
might be done to exclude other diseases, such as anti-
cyclic citrullinated peptide antibodies for rheumatoid
arthritis and uric acid for gout. Synovial fl uid should be
assessed if another arthropathy or septic arthritis is
suspected. In patients with osteoarthritis, synovial fl uid
is sterile, without crystals, and a white-cell count of less
than 1500 cells per μL.
Figure 1: Osteoarthritic joints of the hand, hip, and knee
(A) Osteoarthritis is predominantly identifi ed in the distal interphalangeal and proximal interphalangeal joints—deformations of the distal interphalangeal joints are
clearly visible. (B) Plain radiograph of an osteoarthritic hip joint showing the narrowing of the joint space and clearly visible osteophytes. (C) MRI of an osteoarthritic
knee with clear medial cartilage loss and osteophyte formation, with minor synovial swelling.
A B C

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Markers of tissue damage
Why there is little relation between clinical characteristics
and structural tissue changes in osteoarthritis remains
unclear.14,15 Insensitivity of available monitoring methods
for damage to joint tissue combined with slow progression
of this damage might underlie the discrepancy. Assess-
ment of structural changes is a challenge in studying the
disease and improving treatment modalities.
Early and minimum tissue damage is diffi cult to assess
in vivo. Biopsies for detailed histochemical and
biochemical assessment of cartilage, bone, and synovial
tissue in osteoarthritis are not feasible and are often
contraindicated. Also, tissue changes are often focal and
can be missed by random biopsy procedures.
The exterior of the cartilage can be seen through
arthroscopic procedures.16 However, these procedures
involve invasive techniques, and there is doubt whether
the various stages of degeneration or regeneration
processes of the cartilage can be reliably detected.17
Therefore, at present only surrogate markers, as
indirect measures of the actual destructive process, can
be used for diagnosis and follow-up of tissue damage.
There has been much eff ort to develop new biomarkers,
in the hope that they will improve early diagnosis and
treatment of the disease. However, although promising
in research settings, there is little use for these markers
in daily practice.
Plain radiography is the gold standard in imaging of
osteoarthritic joints, since the technique is inexpensive,
fast, and easily available. Radiography has the advantage
that high-resolution images can be obtained quickly and
routinely under weight-bearing conditions. Restrictions
are radiation exposure and that only calcifi ed bone can be
visualised, which provides an indirect measure of
cartilage thickness without providing information about
synovial tissue. Regulatory agencies (US Food and Drug
Administration, European Medicines Agency) recom-
mend joint-space narrowing on radiographs, in addition
to pain and function, as coprimary endpoints, to establish
the eff ectiveness of disease-modifying drugs.17
Kellgren and Lawrence classifi cation18 has been
developed as a radiological grading of osteoarthritis for
several joints, including knees, hips, and hands.18 The
classifi cation focuses on a sequence of osteophyte
formation, joint-space narrowing, and bone sclerosis,
and provides simple and practical ordinal scales for each
joint. Additional scores have been developed to provide a
further subcategorisation of individual radiographic
features of knee, hip, and hand joints.19 Interactive
computerised measurements have improved standard-
ised assessment of diff erent radiographic features.20–24 As
expected, the more advanced the measurements, the
more time consuming they are and the more complex
analysis becomes. Improvement of scoring methods by
making them more objective and reproducible is
hampered by a lack of standardisation of the image
acquisition. For instance, the position of the joint in the
x-ray beam is crucial for visualisation of the joint-space
width and for the estimation of bone density and
osteophyte area.25 Standardisation of radiographs is now
the crucial step in the reproducibility of radiographic
scoring. Reasonably, several radiographic views,
including the patellofemoral joint for the knee and the
so-called faux profi le image for hip (with backwards
rotated pelvis) improve the relation between clinical and
radiographic changes.26–29
Generally, clinically signifi cant changes in radiographic
scores take at least 1 or even 2 years.30,31 For the knee, the
smallest detectable diff erence of joint-space width is
about 0·20 mm by an expected average annual decrease
of about 0·15 mm.32 More subtle changes can be detected
in a shorter time through the use of advanced
standardisation methods during image acquisition and
more complex analyses, preferably of several images.33–35
Panel: American College of Rheumatology radiological and
clinical criteria for osteoarthritis of the knee and hip
Hand (clinical)
Osteoarthritis if 1, 2, 3, 4 or 1, 2, 3, 5 are present:
1 Hand pain, aching, or stiff ness for most days of
previous month
2 Hard tissue enlargement of two or more of ten selected
joints*
3 Swelling in two or more metacarpophalangeal joints
4 Hard tissue enlargement of two or more distal
interphalangeal joints
5 Deformity of two or more of ten selected hand joints*
Hip (clinical and radiographic)
Osteoarthritis if 1, 2, 3 or 1, 2 ,4 or 1, 3, 4 are present:
1 Hip pain for most days of previous month
2 Erythrocyte sedimentation rate of less than 20 mm in the
fi rst hour
3 Femoral or acetabular osteophytes on radiographs
4 Hip joint space narrowing on radiographs
Knee (clinical)
Osteoarthritis if 1, 2, 3, 4 or 1, 2, 5 or 1, 4, 5 are present:
1 Knee pain for most days of previous month
2 Crepitus on active joint motion
3 Morning stiff ness lasting 30 min or less
4 Age 38 years or older
5 Bony enlargement of the knee on examination
Knee (clinical and radiographic)
Osteoarthritis if 1, 2 or 1, 3, 5, 6 or 1, 4, 5, 6 are present:
1 Knee pain for most days of previous month
2 Osteophytes at joint margins on radiographs
3 Synovial fl uid typical of osteoarthritis (laboratory)
4 Age 40 years or older
5 Crepitus on active joint motion
6 Morning stiff ness lasting 30 min or less
*Ten selected joints include bilateral second and third interphalangeal proximal joints,
second and third proximal interphalangeal joints, and fi rst carpometacarpal joint.

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Apart from plain radiography, other imaging
techniques have been further developed (table 2): CT,
ultrasound, and MRI. Regular CT has similar
disadvantages to plain radiography with clearly higher
radiation exposure, but the advantage is a three-
dimensional image and the option of contrast agents
(contrast enhanced CT) to visualise cartilage in addition
to bone. Bone is innervated and evidence is accruing
that bone changes might be an important source of
pain in osteoarthritis.36 Assessment of CT has shown a
strong relation between the dissolving of cystic bone
areas and pain relief after treatment of end-stage
osteoarthritis.37 Techniques are still improving,38,39 but
are unlikely to become the standard.
Ultrasound has the advantages that it also images soft-
tissue structures (such as synovial tissue) in several
planes, it does not need contrast agents, and it allows the
visualisation of movement.40 Limitations exist in the
depth that the signal can penetrate and the sites (tissues)
that can be assessed. Most importantly, ultrasound is
very dependent on the experience and skills of the user.
The use of power doppler signal to image vascularisation41
and specifi c integrated techniques to assess cartilage
thickness42 enhances its applications. Although the use of
ultrasound to detect osteoarthritic pathological changes43
(specifi cally in hand joints44,45) is increasing, its ultimate
role in osteoarthritis is not certain.
MRI provides objective quantitative assessment of
morphology (volume, area, and thickness) and integrity
(quality) of articular cartilage.46,47 A broad range of
sequences and scoring systems allow for sensitive
analyses of periarticular soft tissues in addition to cartilage
and bone. Important limitations are cost, acquisition time
(on average 45 min), complexity of the more advanced
techniques, and time for whole-organ analyses. These
limitations hamper the use of MRI for the imaging of
osteoarthritis, although its value in identifying bone-
marrow and meniscal lesions is well established.48
The use of fat-suppressed spoiled gradient echo
sequences produces a high cartilage signal and low signal
from adjacent joint fl uid, and at present is the standard
for quantitative morphological imaging of cartilage.46,49
The availability of higher fi eld strengths, up to 3 tesla,
makes these measurements even more accurate.32
Several semiquantitative scoring systems (table 2)
have been developed that focus on the size and location
of the lesions, and on subchondral, cartilaginous, bone,
and other abnormalities. Apart from tissue-specifi c
scores, whole-organ scores have been developed, such
as the knee osteoarthritis scoring system,50 the whole-
organ magnetic resonance imaging score,51 and the
Boston Leeds osteoarthritis knee score,52 each with their
own advantages.32
More complex acquisition sequences have been
developed that focus on cartilage quality; T2 MRI relaxation
time is related to collagen orientation and density of
articular cartilage;53 a possible relation with cartilage
degeneration has been shown.54,55 Also, the T1ρ MRI
technique provides information that allows proteoglycan
distribution in articular cartilage to be mapped.53,56 The
negatively charged proteoglycans are responsible for the
fi xed charged density of the cartilage matrix that makes
sodium MRI57 and delayed gadolinium-enhanced MRI of
cartilage useful for visualising proteoglycan content.58
When given intravenously, gadolinium-diethylenetriamine
penta-acetic acid homes in on regions of cartilage with low
proteoglycan content.59 Some clinical applications have
shown its value, but variables such as body-mass index,
Knee Hip Hand
Occurrence Age, sex, physical activity, body-mass index (including
obesity), intense sport activities, quadriceps strength, bone
density, previous injury, hormone replacement therapy
(protective), vitamin D, smoking (protective or deleterious),
malalignment (including varus and valgus), genetics
Age, physical activity, body-mass index (including
obesity), previous injury, intense sport activities, genetics
(including congenital deformities)
Age, grip strength, occupation, intense sport
activities, genetics
Progression Age, body-mass index (including obesity), vitamin D,
hormone replacement therapy (protective), malalignment
(including varus and valgus), chronic joint eff usion, synovitis,
intense sport activities, subchondral bone oedema on MRI
Age, symptomatic activity, sex, intense sport activities Unknown
Table 1: Selected risk factors for the occurrence and progression of osteoarthritis in knees, hips, and hands
Figure 2: Schematic drawing of an osteoarthritic joint
The diff erent tissues involved in clinical and structural changes of the disease are shown on the left. Note that
cartilage is the only tissue not innervated. On the right the bidirectional interplay between cartilage, bone, and
synovial tissue involved in osteoarthritis is shown, and the two-way interaction between this interplay and the
ligaments and muscles. In the interplay between cartilage, bone, and synovial tissue one of the tissues might
dominate the disease, and as such should be targeted for treatment.
Weakening and
contracture of
ligaments
and muscles
Inflammation of
synovial tissue
Cartilage damage
and loss
Outgrowth of bone
(osteophytes)
and attrition
Changes in subchondral
bone (sclerosis and cysts)

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2119
severity of synovitis, and subchondral bone alterations,
make use of the technique complex.60–62 Most of the
developments in MRI involve the knee, much less research
has been done on hips63 and hands.64
In general, MRI sequences and scoring systems
provide good quantitative analyses of several joint
structures, with more advanced techniques providing
information about cartilage quality. Unfortunately, cost,
acquisition, and analytical time restrict developments of
these techniques in research settings and their use in
daily clinical practice. In the future, MRI assessments
in larger clinical trials might become standard; in
today’s practice they have value only for specifi c
diagnostic questions.
Biochemical markers of joint metabolism, disease, or
both are molecules or molecular fragments that are
released into biological fl uids (synovial fl uid, blood, and
urine) from extracellular matrix turnover (synthesis and
breakdown), such as collagen or proteoglycan fragments
(or neo-epitopes) and cellular metabolism (eg, proteases
or cytokines) of articular cartilage, subchondral bone,
and synovial tissue. Biochemical markers seemed to help
understand the pathophysiology of osteoarthritis and in
the prediction of structural changes. However,
breakthroughs have been sparse and there is doubt about
how these markers might be used.65 We lack suffi cient
knowledge about molecular validity, systemic origin,
metabolism, and kinetics (absorption, distribution, and
excretion) from many biochemical markers.66,67 The same
marker might increase as well as decrease, dependent on
the point in the degradation process.
Urine and blood are the most relevant compartments
in which to assess biomarkers. There are few studies of
biomarkers reporting on their diagnostic and prognostic
properties, their relation to burden of disease, and their
relation to eff ectiveness of intervention. The relation of
biomarkers with structural changes is in general
better understood than their relation with clinical
characteristics.68
Table 3 lists the most reported biomarkers and their
performance. Markers of cartilage degradation, such as
CTXII in urine and COMP in serum, have been assessed
extensively and show a moderate to good relation with
clinical and radiographic variables of osteoarthritis.
Markers of bone metabolism are less eff ective,
presumably because of the size of the bone compartment
(mostly outside the joints) and the high turnover of bone.
Not enough is known about markers of bone metabolism,
which might have an important role in osteoarthritis
since bone changes might be an important source of
pain.36,69 Markers of synovial tissue metabolism are the
least studied, but produce positive results, underscoring
a role for infl ammation in osteoarthritis. Homogeneity
of the studied population and standardisation of sample
collection might improve the relation between a
biomarker and clinical or radiographic characteristics,
since diurnal rhythms and eff ects of exercise have been
described for several markers.70–72
None of the presently available biomarkers are
suffi ciently eff ective to aid diagnosis or prognosis of
osteoarthritis in individual or small numbers of
patients, nor are any so consistent that they could
Primary use Analyses Advantages Disadvantages
Plain radiograph* Cartilage thickness (Semi)quantitative Low cost, easy applicable Indirect, two-dimensional image of a
three-dimensional problem
CT
Standard* Bone characteristics Semiquantitative Three dimensional Radiation exposure, only bone
CECT As standard plus cartilage volume Semiquantitative Three dimensional, information on cartilage As standard plus contrast agent needed
Ultrasound
Standard* Infl ammation Impression Cheap User dependent
Power doppler Vascularisation Semiquantitative Direct measure Relative importance for osteoarthritis
MRI
Standard SPGR* Cartilage morphology Quantitative Three dimensional, quantitative Time-consuming analyses
T2 MRI relaxation Collagen distribution Semiquantitative Information on cartilage quality Complex interpretation
T1ρProteoglycan distribution Semiquantitative Information on cartilage quality Complex interpretation
23Na MRI FCD/proteoglycan content Semiquantitative Information on cartilage quality Field strength ≥3T
dGEMRIC FCD/proteoglycan content Semiquantitative Information on cartilage quality, early changes Contrast agent needed
MRI whole-organ scoring
KOSS ·· Semiquantitative Whole-organ score Time consuming, observer variance
WORMS ·· Semiquantitative Whole-organ score Time consuming, observer variance
BLOKS ·· Semiquantitative Whole-organ score Time consuming, observer variance
CECT=contrast-enhanced CT. SPGR=spoiled gradient echo. FCD=fi xed charge density. dGEMRIC=delayed gadolinium-enhanced MRI of cartilage. KOSS=knee osteoarthritis scoring system. WORMS=whole-organ
magnetic resonance imaging score. BLOKS=Boston Leeds osteoarthritis knee score. *Techniques that have a more common clinical and research applications for the assessment of cartilage (and bone), bone, and
synovial infl ammation, as well as quantitative cartilage morphology (at present the most used MRI modality in clinical trials).
Table 2: Imaging techniques for assessment of tissue-structure changes in osteoarthritis

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function as an outcome in clinical trials. More needs to
be understood about biochemical markers, and
combinations thereof, to make these markers of use in
general clinical practice.
Treatment
In early osteoarthritis, pain and stiff ness dominate the
other symptoms.73 Treatment should therefore focus on
the reduction of pain and stiff ness and on the maintenance
and improvement of functional capacities. Furthermore,
prevention of progression of joint damage and
improvement of quality of life are long-term goals. There
are three treatment modalities: non-pharmacological,
pharmacological, and surgical. In many patients these
modalities are combined, tailored to individual needs and
risk factors. The European League Against Rheumatism
and the Osteoarthritis Research Society International
have published evidence-based guidelines for the
treatment of osteoarthritis.74–78 Daily practice is based on
these guidelines and updates from published work.
Self-management interventions can be defi ned as
patient centred and as designed to foster active participation
of patients to promote wellbeing and to manage symptoms.
These programmes in chronic diseases are now thought
key elements of good-quality care.79 In long-term disease
management these interventions seem to be eff ective and
necessary for the compliance of patients, although there
are few reported benefi ts.80
Symptoms can be reduced by providing the patient
with information about osteoarthritis, its symptoms, the
objectives of its treatment, and the importance of
changes in lifestyle—although the eff ect size of these
interventions is small (<0·20).77,78 Pain has many
components, and is also aff ected by comorbidities, such
as sleeping problems, loneliness, and mood disorders;81
improvement of mental and social wellbeing is therefore
also a target in some patients.82
There is evidence for a positive eff ect of exercise, pacing
of activities, joint protection, weight reduction, and other
measures to unload damaged joints (eff ect
size 0·20–0·50).76–78 It is unclear if particular exercises are
more benefi cial than others for specifi c joints. Probably
the best exercises should be established through
personalised advice, which takes into account individual
factors. Exercises that strengthen muscles and improve
aerobic condition are most eff ective, at least for
osteoarthritis of the hip and knee.83
Weight reduction is not easy, but quite eff ective,
especially in osteoarthritis of the knee. Randomised
controlled trials have shown that weight reduction has
led to lessening of pain and improvement of physical
function,84 and recent research has also shown structural
improvement of cartilage85 and positive changes in
biomarkers of cartilage and bone.86
Unpopular measures such as braces, cranes, and other
forms of joint protection might have a slight eff ect and
are generally cost eff ective.87,88 These measures should be
discussed with the individual patient.
Commonly used treatment modalities are insoles,
lasers,89 transcutaneous electrical nerve stimulation,90
ultra sound,91 electrotherapy,92 or acupuncture,93 but
evidence is scarce, as is the eff ect size. However,
applications of heat and ice are easy to use and
quite eff ective.94
Paracetamol is the fi rst-choice oral analgesic for
osteoarthritis because of its safety and eff ectiveness,74–76
but patients have often used paracetamol with little eff ect
before they visit their physician. Sometimes a dose
increase to an optimum regimen for the individual
patient is a therapeutic option, but often a non-steroidal
anti-infl ammatory drug (NSAID) is added or substituted.
The use of stronger analgesics, such as weak opioids and
narcotic analgesics, is only indicated when other drugs
(such as NSAIDs) have been ineff ective or are
contraindicated.77
NSAIDs can be used in patients with symptomatic
osteoarthritis of the hand, hip, or knee, preferably at the
lowest eff ective dose and for the shortest duration.76,77 In
patients with cardiovascular risk factors all NSAIDs,
Diagnostic
value
Relation to
burden of
disease
Prognostic
value
Relation to
effi cacy of
treatment
Overall
positive
proportion
Cartilage degradation
CTXII in urine* 12/13 16/25 17/23 4/5 74%
COMP in serum* 9/12 15/26 6/17 1/2 54%
Coll 2-1 (NO2)† in urine and serum 7/8 2/6 2/4 ·· 61%
KS in serum 1/2 3/8 3/5 1/2 47%
YKL-40 in serum 1/3 5/12 0/4 1/1 35%
C2C in urine and serum 1/1 3/9 0/4 1/3 29%
C1,2C in urine and serum ·· 1/6 0/4 0/2 8%
Cartilage synthesis
PIIANP in serum* 2/2 1/4 2/3 0/1 50%
PIICP in serum ·· 3/7 0/4 ·· 27%
CS846 in serum 0/1 1/7 0/3 ·· 9%
Bone degradation
NTX-I in urine and serum* 1/2 1/1 2/5 2/2 60%
(D)PYR† in urine 2/3 6/15 0/10 2/2 33%
CTXI in urine and serum 2/4 1/16 1/6 0/1 15%
Bone synthesis
OC in serum* 1/5 2/12 2/6 1/2 24%
BSP in serum 2/2 1/3 0/2 ·· 43%
PINP in serum 0/1 1/4 0/4 ·· 11%
Synovium degradation
HA in serum* 7/9 7/22 8/11 1/3 51%
Glc-Gal-PYR in urine 2/2 3/4 ·· 0/1 71%
Synovial synthesis
PIIINP in serum 1/1 2/4 0/2 ·· 43%
Data are n/N unless otherwise stated. Biomarkers with less than fi ve reports are not included. Data from van Spil and
colleagues.68 *The most relevant and best performing commercial biomarkers. †Combined biomarkers: Coll 2-1 with
Coll 2-1 NO2 and PYR with D-PYR.
Table 3: Overview of published work on biomarkers over the past 5 years for knee and hip osteoarthritis

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2121
including both non-selective and cyclo-oxygenase-2
selective drugs should be used with caution and are
sometimes contraindicated; the individual drug
characteristics seem to be more relevant than the class of
drug.78 In patients with high gastrointestinal risk, either
a cyclo-oxygenase-2 selective drug or a non-selective
NSAID with co-prescription of a proton pump inhibitor
for gastroprotection, might be considered. A possible
additional argument for the use of selective cyclo-
oxygenase-2 drugs was reported in a trial comparing
celecoxib versus omeprazole and diclofenac in patients
with osteoarthritis and rheumatoid arthritis.95 Both drugs
were equally eff ective for the treatment of upper
gastrointestinal problems, but celecoxib was better than
diclofenac and omeprazole in the reduction of all
gastrointestinal events (especially clinically signifi cant
anaemia of presumed gastrointestinal origin). Another
attempt to reduce the gastrointestinal and cardiovascular
side-eff ects of NSAIDs is the linking of an NSAID with a
nitric-oxide-donating group, which creates a cyclo-
oxygenase-inhibiting nitric-oxide donor. Nitric oxide
thus might help to maintain gastric integrity and
cardiovascular homoeostasis.96,97 Topical NSAIDs are
recommended as alternative or adjunctive treatment and
have been reported to be as eff ective as and possibly
safer than oral NSAIDs.98
The use of opioid analgesics for the treatment of
osteoarthritis has risen, but a real improvement in
osteoarthritic pain that has not responded to NSAIDs
has been noted only with strong opioids (oxymorphone,
oxycodone, oxytrex, fentanyl, morphine sulphate).99 This
use is reserved for exceptional circum stances, such as
patients awaiting planned surgery; there is a high (over
30%) withdrawal rate of patients treated, because of
nausea, constipation, dizziness, somnolence, and
vomiting.99
The effi cacy of weaker opioids (tramadol or codeine) has
not been assessed in long-term trials. Paracetamol–
codeine combinations provide a small (5%), but statistically
signifi cant (p<0·05), benefi t over paracetamol alone, but
are associated with more adverse events.100 In the absence
of convincing evidence for their safe and eff ective use,
concerns about risks of dependence or addiction to opiates
aff ects the prescription of these drugs.77
Patients sometimes use a group of symptomatic slow-
acting drugs for osteoarthritis—ie, glucosamine sulphate,
chondroitin sulphate, hyaluronic acid—and, less
commonly, avocado soybean unsaponifi able, and
diacerhein. Randomised trials with glucosamine sulphate
have been debated heavily—there is concern about bias,
heterogeneity of outcomes, and eff ect size.78 Most
published studies show that glucosamine sulphate has a
benefi cial eff ect on pain, with eff ect size ranging
between 0·30 and 0·87,78 but no eff ect on function and
controversial eff ects on structure modifi cation.101,102
Whether glucosamine sulphate is eff ective in
osteoarthritis remains undetermined.103 In the USA,
glucosamine hydrochloride has been assessed thoroughly,
but no benefi cial eff ect has been reported.
There is less, but still confl icting, evidence for the
eff ectiveness of chondroitin sulphate on pain and
function.104 Avocado soybean unsaponifi ables have been
assessed for the treatment of osteoarthritis of the knee
and hip, but not of the hand. This treatment was eff ective
in relieving pain and improving function in hip more
than in knee, osteoarthritis (eff ect size 0·01–0·76).105
Avocado soybean unsaponifi ables are used in some
regions of the world, but are unknown in others.
Diacerein is reported to have slow-acting, but persistent,
symptomatic relief in patients with osteoarthritis (eff ect
size for pain 0·24; 95% CI 0·08–0·39).78
Intra-articular injection of long-acting glucocorticoids
is an eff ective treatment of infl ammatory fl ares of
osteoarthritis (eff ect size for pain relief 0·58); the eff ect is
greatest after 1 week, and diminishes thereafter.106 After
injection of the weight-bearing large joints (ankle, knee,
hip) the eff ectiveness of the injection can be enhanced by
complete bed rest of the treated joint for 72 h.107
Hyaluronic acid has varying eff ectiveness when used
for intra-articular injections for the treatment of
osteoarthritis of the knee. Diff erent products with
diff erent injection regimens (up to fi ve consecutive
weekly injections) have been used (eff ect size up
to 0·39).108 Investigators have suggested that the high
molecular-weight products (even cross-linked
components, such as Hylan G-F 20) need to be injected
less often and improve eff ectiveness.78,109,110
A Cochrane review of surgical lavage and debridement
in osteoarthritis of the knee111 showed no benefi t in the
short or long term compared with placebo; in general
this procedure is not advised. Other surgical interventions
include osteotomy, joint fusion, joint distraction, and
joint replacement. Joint replacement is very cost eff ective
in patients with severe symptoms or functional
limitations associated with a reduced quality of life,
despite conservative treatment.77
New developments
New discoveries about the pathophysiology of
osteoarthritis prompt the division of the disease into
distinguishable phenotypes. Delineating the diff erent
clinical and structural phenotypes of the disease will
improve understanding—of disease in patients with
pain, trauma, or obese-dominated clinical phenotypes
(table 4 lists our attempt)—and will also allow specifi c
targeted treatment in those in whom structural changes
in either cartilage, bone, or synovial tissue dominate the
disease. Although these phenotypes are not yet fully
characterised, distinguishing diff erent phenotypes could
herald the start of further discussions. Lack of in-depth
understanding of disease pathogenesis and the
misconception that all forms of osteoarthritis are the
same and have the same clinical and structural
characteristics might restrict further development of

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diagnosis, treatment, and monitoring of the many forms
of the disease. A consensus on subgrouping osteoarthritis
into such phenotypes will take time.
In the structure phenotype, after entering a point of no
return in which damage of the cartilage matrix over-rides
synthesis, a vicious cycle of progressive damage ensues
in which impaired biomechanical properties result in
further damage.5–7 Autocrine loops of soluble factors
released by the triggered chondrocytes112–115 trigger an
infl ammatory response that accelerates the breakdown
process.8,9 This infl ammatory activity is enhanced by the
accelerated release of catabolic cartilage constituents that
provide an additional vicious cycle in the process of tissue
destruction. The stiff ening of the subchondral bone
(sclerosis) reported in the more advanced stages of the
disease increases stresses in the overlying cartilage and
adds to the damage. Also, in the early phase, subchondral
bone changes might cause cartilage damage and might
even precede it.10,11 Soluble factors produced locally in
subchondral bone are potential candidates to act on deep-
zone articular chondrocytes to promote abnormal
remodelling and metabolism of deep cartilage, leading to
its breakdown.116–118 This breakdown is facilitated by the
interaction between bone and cartilage that was originally
thought to be a tight interface, but is now recognised as
allowing soluble factors to migrate between bone and
cartilage.119–121 Moreover, angiogenesis has been identifi ed
at the junction of articular hyaline cartilage and adjacent
subchondral bone;122,123 and therefore tissue damage
of the whole joint is also biochemical and not
merely mechanical.124
In the age phenotype, chondrocytes sense alterations
in mechanical stresses and, dependent on the context,
respond with anabolic or catabolic biochemical
processes.125,126 This cartilage degeneration is not merely
mechanically induced wear and tear, but a complex of
biochemical interactions.
Ageing alters the response of chondrocytes: aged
chondrocytes produce more infl ammatory cytokines,
tissue degrading enzymes, and growth factors.127
Moreover, advanced glycation endproducts (AGEs),
which accumulate in cartilage, can bind to specifi c
receptors (receptor of advanced glycation endproducts;
RAGE) expressed on chondrocytes, increasing their
catabolic activity.128,129 AGE induces alteration of bio-
mechanical properties by stiff ening the cartilage, which
makes it brittle and more prone to damage. There is no
clear clinical evidence of how AGE contributes to the
development and progression of osteoarthritis.130
Development of soluble AGE receptors, sRAGE, that
bind to AGEs and thereby inhibit the activation of cell-
surface RAGE, showed effi cacy in the treatment of
vascular complications in animal models of diabetes.
Also, prevention or reversal of AGE formation by diet or
specifi c cleavage of AGE-crosslinks is subject to study
and might become feasible.
In the obesity phenotype, the overload eff ect on joint
cartilage might, in part, explain the greater risk of
osteoarthritis in overweight people. Advances in the
physiology of adipose tissue provide further information
about the relation between obesity and osteoarthritis.131
Indeed, a positive association between obesity and
osteoarthritis has been reported for non-weight-bearing
joints, such as those of the hands, and not only knee
joints.132 These reports suggest that joint damage might
be caused by systemic factors such as adipose factors, the
so-called adipokines, which might provide a metabolic
link between obesity and osteoarhtritis,133 and which, in
addition to weight loss, could become a specifi c
therapeutic target.
Growing knowledge of the pathogenetic mechanisms
involved in osteoarthritis will lead to the development of
new classes of drugs for targeted treatment; many new
pharmacological approaches in the management of
osteoarthritis are under development.134 Calcitonin, a
hormone of calcium homoeostasis, inhibits osteoclast
activity and also has a direct eff ect on cartilage by the
inhibition of matrix metalloproteinase activity. In a pilot
study in patients with osetoathritis,135 CTXII, a degradation
marker, decreased after patients were given oral
calcitonin. At present, calcitonin is under investigation in
a long-term randomised controlled trial.
Nitric oxide is one of the catabolic mediators in cartilage
and synovium. Inducible nitric oxide synthase is
upregulated in osteoarthritis and in various pain states.
At present, a study is assessing a specifi c inducible nitric
Post-traumatic
(acute or repetitive)
Metabolic Ageing Genetic Pain
Age Young (<45 years) Middle-aged (45–65 years) Old (>65 years) Variable Variable
Main causative feature Mechanical stress Mechanical stress, adipokines,
hyperglycaemia, oestrogen/
progesterone imbalance
AGE, chondrocyte
senescence
Gene related Infl ammation, bony changes,
aberrant pain perception
Main site Knee, thumb, ankle, shoulder Knee, hand, generalised Hip, knee, hand Hand, hip, spine Hip, knee, hand
Intervention Joint protection, joint
stabilisation, prevention of falls,
surgical interventions
Weight loss, glycaemia control, lipid
control, hormone replacement
therapy
No specifi c intervention,
sRAGE/AGE breakers
No specifi c intervention,
gene therapy
Pain medication,
anti-infl ammatory drugs
Osteoarthritis is not one disease, and might benefi t from the recognition of its diff erent phenotypes. AGE=advanced glycation endproducts. sRAGE=soluble receptor for advanced glycation endproducts.
Table 4: Proposal for diff erentiation of clinical phenotypes of osteoarthritis

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2123
oxide synthase inhibitor (SD-6010) in patients with knee
osteoarthritis.
Studies with bisphosphonates were done with the aim
of inhibiting increased bone turnover in osteoarthritis;
however, they were negative with regard to symptoms
and radiological progression, although biochemical
markers of cartilage turnover decreased.136
Advances in pain neurobiology have shown the role of
supraspinal pathways and downstream neuro trans-
mitters and eff ectors in chronic pain. Antibodies to nerve
growth factor have been developed by several companies.
The benefi t-to-risk ratio of these compounds is not yet
clear and needs to be assessed further.137 Initial studies in
patients with osteoarthritis have shown a slight clinical
benefi t of the centrally acting compound duloxetine in
patients with chronic painful osteoathritis.138 Duloxetine
is a serotonin–norepinephrine reuptake inhibitor used in
the treatment of depression, and also assessed in
fi bromyalgia and diabetic peripheral neuropathy.
Contributors
All authors contributed equally to the search of published work, the
discussions, and writing. All authors gave their fi nal approval for the
decision to submit for publication.
Confl icts of interest
We declare that we have no confl icts of interest.
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